The liver is the primary source of cholesterol produced in humans. Bile acid salts are major end-products of cholesterol catabolism, which aid in fat digestion. A 4-6 gram bile salt pool is maintained in the body and about 5% of this bile acid pool is normally excreted daily.
Bile acid salt sequestrants increase the rate of bile acid salt excretion and since the bile acid salts inhibit the conversion of cholesterol to bile acid salts, their removal increases the rate of hepatic metabolism of cholesterol. In addition, however, a compensatory increase in the rate of hepatic biosynthesis of cholesterol occurs to maintain hepatic cholesterol balance and more importantly a resultant lowering of serum and arterial cholesterol and thus lowering of low density liporotein is observed. The exact mechanism for this lowering is not known.
The bile acid sequestrants cholestyramine (Cuemid.RTM., Questran.RTM.), colestipol (Colestid.RTM.), and DEAE-Sephadex (Secholex.RTM., Polidexide.RTM.) are currently available. The disadvantages of cholestyramine are its amine-like odor and unpleasant mouth feel. The mouth feel is characterized by a gritty, sand-like feel. Although colestipol is odorless, the intrinsic mouth-feel characteristics of this resin are similar to those of cholestyramine. Also, large doses (8-16 gr. per day) of cholestyramine are required to reduce serum cholesterol, which causes constipation in some people.
Certain water soluble, non-cross-linked cationic polymers are known bile acid salt sequestrants and serum cholesterol lowering agents, e.g., ionenes of the formula: ##STR1## as claimed in U.S. Pat. No. 4,027,009 and disclosed in "Atheriosclerosis", 37, 353-360 (1980). The latter reference discloses another water soluble, non-cross-linked polymer, the quaternary amine poly(diallyldimethylammonium chloride), ##STR2## as a cholesterol lowering agent. These polymers when tested in dogs are effective in lowering cholesterol, but are non-cross-linked and toxic.
An objective of tnis invention is to develop cholesterol lowering agents without unpleasant mouth-feel characteristics.
Another objective of this invention is to develop cholesterol lowering agents that can be administered in a pill or capsule form or incorporated in food or candy.